Oxidative stress and glutathione (GSH) imbalance are major contributors to the pathogenesis of diabetic nephropathy. Circulating monocytes participate to this process since these cells carry a high oxidative burden and are found in diabetic renal tissue. Current options for the treatment of oxidative stress in diabetic nephropathy are limited and only partially effective, thus interest in the development of new strategies is high. N-acetylcysteine (NAC) and the milk thistle (MTh) plant flavonolignans are nutritional supplements with complementary antioxidant properties. Both supplements are capable of neutralizing directly toxic free radicals but, more importantly, NAC is substrate for the intracellular generation of GSH and the MTh flavonolignans are inducers of many cellular enzymes participating in GSH metabolism, including GSH-reductase (GSH-R), GSH-peroxidase (GSH-Px), GSH-S-transferases (GST) and superoxide dismutase (SOD). We propose that combined oral supplementation of NAC and MTh flavonolignans will reduce proteinuria and urinary and systemic manifestations of oxidative stress and inflammation, which are characteristically observed in patients with type 2 diabetes mellitus (T2DM) and related nephropathy. We expect these effects to be achieved with minimal or no side effects, and with good patient tolerance. To test this hypothesis, we propose a double-blind randomized, placebo-controlled, five-arm pilot study which includes a dose ranging component in patients with T2DM and established nephropathy. Intervention will consist of the individual and combined oral administration of one level of NAC and two levels of MTh flavonolignans or placebo for three months. The intervention groups are: (A) placebo;(B) NAC 600 mg BID;(C) Siliphos&#63194;480 mg BID;(D) NAC 600 mg BID + Siliphos&#63194;480 mg BID;and (E) NAC 600 mg BID + Siliphos&#63194;960 mg BID. The primary outcome measure will be urinary excretion of albumin, a marker of glomerular injury. Secondary outcome measures will be alpha-1 microglobulin, a marker of tubular injury, and urinary excretion of inflammatory cytokines and C-C chemokines, i.e. markers of renal inflammation. In plasma and in peripheral blood monocytes from the same patients, we will analyze GSH content and activity of GSH metabolizing enzymes. In addition, we will analyze the plasma and urine glycoproteome, with focus on those glycoproteins serving as inflammatory cell messengers and hormones. These variables will be monitored in relation to both treatment allocation and prevalent blood and urine levels of the active treatment. Throughout the trial, we will monitor the safety and tolerability of this combination treatment.